Anxiety disorders in children are prevalent and are increasingly recognized as a major public health concern. In addition to the psychological suffering and disability associated with childhood anxiety disorders, these symptoms are commonly associated with comorbid depressive symptoms, exacerbate other medical illnesses, and increase the later risk to develop anxiety disorders, depression and comorbid drug and alcohol abuse. Despite the importance of generalized anxiety disorder (GAD) occurring during childhood, little is known about the brain alterations that mediate its development and pathophysiology. The overall aim of this proposal is to build on our work in young nonhuman primates by identifying intermediate brain phenotypes that are linked to early human childhood GAD. The hypothesis that altered prefrontal-amygdala connectivity and altered amygdala chronometry is associated with symptoms of GAD will be evaluated with structural and functional MRI, in conjunction with relevant physiological and behavioral measures. While these methods have been commonly used in adults and less frequently in adolescents, very few studies have examined these measures in relation to clinically significant anxiety in pre-adolescent children. This is particularly important since anxiety and depression in adults and adolescents frequently begins as clinically significant anxiety earlier in life. Understanding alterations in the neural circuitry that underlie the expression of GAD in preadolescent children will provide a rationale for using biomarkers aimed at early detection. Specifically, these data will lay the foundation for prospective longitudinal studies examining the utility of assessing amygdala chronometry and prefrontal-amygdala connectivity in relation to the early detection and treatment of these childhood illnesses. This proposal is intended to fund the initial stages of this research with the long-term plan to obtain a very large sample of children with GAD. Because of the heterogeneity of comorbid symptoms, obtaining a large sample will allow us to parse GAD and associated symptoms in relation to distinct underlying neural alterations. This has the potential to provide new insight into the current conceptualization of GAD and will set the stage for novel brain based classification of symptom patterns in children with clinically significant anxiety. The opportunities from performing these studies in GAD children are numerous. They will provide a developmental framework for understanding the structure and function of brain circuits that are associated with the earliest expression of psychopathology. In addition, this knowledge may provide a rationale for the development of psychosocial and pharmacologic interventions that target key components of the involved neural circuit and take into account the plasticity of the developing child's brain. Early more effective interventions tha are based on a sound neurodevelopmental rationale hold the promise for the prevention of later adolescent and adult anxiety, depression and substance abuse. PUBLIC HEALTH RELEVANCE: Anxiety disorders in children are prevalent and are increasingly recognized as a major public health concern. In addition to the psychological suffering and disability associated with childhood generalized anxiety disorder (GAD), these symptoms are commonly associated with depressive symptoms, exacerbate comorbid medical illnesses, and increase the risk to develop drug and alcohol abuse. The proposed studies are aimed at understanding the brain alterations associated with childhood GAD so that early diagnosis can be improved and more effective interventions can be developed.